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High expression of insulin receptor on tumor-associated blood vessels in invasive bladder cancer predicts poor overall and progression-free survival


Roudnicky, Filip; Dieterich, Lothar C; Poyet, Cedric; Buser, Lorenz; Wild, Peter; Tang, Dave; Camenzind, Peter; Hsien Ho, Chien; Otto, Vivianne I; Detmar, Michael (2017). High expression of insulin receptor on tumor-associated blood vessels in invasive bladder cancer predicts poor overall and progression-free survival. Journal of Pathology, 242(2):193-205.

Abstract

Bladder cancer is a frequently recurring disease with a very poor prognosis when progressed to invasive stages, and tumor-associated blood vessels play a crucial role in this process. In order to identify novel biomarkers associated with progression, we isolated blood vascular endothelial cells (BECs) from human invasive bladder cancers and matched normal bladder tissue, and found that tumor-associated BECs greatly upregulated the expression of insulin receptor (INSR). High expression of INSR on BECs of invasive bladder cancers was significantly associated with shorter progression-free and overall survival. Furthermore, increased expression of the INSR ligand IGF-2 in invasive bladder cancers was associated with reduced overall survival. INSR may therefore represent a novel biomarker to predict cancer progression. Mechanistically, we observed pronounced hypoxia in human bladder cancer tissue, and found a positive correlation between the expression of the hypoxia marker gene GLUT1 and vascular INSR expression, indicating that hypoxia drives INSR expression in tumor-associated blood vessels. In line with this, exposure of cultured BECs and human bladder cancer cell lines to hypoxia led to increased expression of INSR and IGF-2, respectively, and IGF-2 increased BEC migration through the activation of INSR in vitro. Taken together, we identified vascular INSR expression as a potential biomarker for progression in bladder cancer. Furthermore, our data suggest that IGF-2 / INSR mediated paracrine crosstalk between bladder cancer cells and endothelial cells which is functionally involved in tumor angiogenesis and my thus represent a new therapeutic target.

Abstract

Bladder cancer is a frequently recurring disease with a very poor prognosis when progressed to invasive stages, and tumor-associated blood vessels play a crucial role in this process. In order to identify novel biomarkers associated with progression, we isolated blood vascular endothelial cells (BECs) from human invasive bladder cancers and matched normal bladder tissue, and found that tumor-associated BECs greatly upregulated the expression of insulin receptor (INSR). High expression of INSR on BECs of invasive bladder cancers was significantly associated with shorter progression-free and overall survival. Furthermore, increased expression of the INSR ligand IGF-2 in invasive bladder cancers was associated with reduced overall survival. INSR may therefore represent a novel biomarker to predict cancer progression. Mechanistically, we observed pronounced hypoxia in human bladder cancer tissue, and found a positive correlation between the expression of the hypoxia marker gene GLUT1 and vascular INSR expression, indicating that hypoxia drives INSR expression in tumor-associated blood vessels. In line with this, exposure of cultured BECs and human bladder cancer cell lines to hypoxia led to increased expression of INSR and IGF-2, respectively, and IGF-2 increased BEC migration through the activation of INSR in vitro. Taken together, we identified vascular INSR expression as a potential biomarker for progression in bladder cancer. Furthermore, our data suggest that IGF-2 / INSR mediated paracrine crosstalk between bladder cancer cells and endothelial cells which is functionally involved in tumor angiogenesis and my thus represent a new therapeutic target.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
04 Faculty of Medicine > University Hospital Zurich > Urological Clinic
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:14 March 2017
Deposited On:12 Apr 2017 14:06
Last Modified:02 Jul 2017 05:29
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0022-3417
Publisher DOI:https://doi.org/10.1002/path.4892
PubMed ID:28295307

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Embargo till: 2018-03-15

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